Mutations in a novel gene, NPHP3, cause adolescent nephronophthisis, tapeto-retinal degeneration and hepatic fibrosis

Heike Olbrich, Manfred Fliegauf, Julia Hoefele, Andreas Kispert, Edgar Otto, Andreas Volz, Matthias T. Wolf, Gürsel Sasmaz, Ute Trauer, Richard Reinhardt, Ralf Sudbrak, Corinne Antignac, Norbert Gretz, Gerd Walz, Bernhard Schermer, Thomas Benzing, Friedhelm Hildebrandt, Heymut Omran

Research output: Contribution to journalArticle

258 Citations (Scopus)

Abstract

Nephronophthisis (NPHP), a group of autosomal recessive cystic kidney disorders, is the most common genetic cause of progressive renal failure in children and young adults. NPHP may be associated with Leber congenital amaurosis, tapetoretinal degeneration, cerebellar ataxia, cone-shaped epiphyses, congenital oculomotor apraxia and hepatic fibrosis. Loci associated with an infantile type of NPHP on 9q22-q31 (NPHP2), juvenile types of NPHP on chromosomes 2q12-q13 (NPHP1) and 1 p36 (NPHP4) and an adolescent type of NPHP on 3q21-q22 (NPHP3) have been mapped. NPHP1 and NPHP4 have been identified, and interaction of the respective encoded proteins nephrocystin and nephrocystin-4 has been shown. Here we report the identification of NPHP3, encoding a novel 1,330-amino acid protein that interacts with nephrocystin. We describe mutations in NPHP3 in families with isolated NPHP and in families with NPHP with associated hepatic fibrosis or tapeto-retinal degeneration. We show that the mouse ortholog Nphp3 is expressed in the node, kidney tubules, retina, respiratory epithelium, liver, biliary tract and neural tissues. In addition, we show that a homozygous missense mutation in Nphp3 is probably responsible for the polycystic kidney disease (pcy) mouse phenotype. Interventional studies in the pcy mouse have shown beneficial effects by modification of protein intake and administration of methylprednisolone, suggesting therapeutic strategies for treating individuals with NPHP3.

Original languageEnglish (US)
Pages (from-to)455-459
Number of pages5
JournalNature Genetics
Volume34
Issue number4
DOIs
StatePublished - Aug 1 2003

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Retinal Degeneration
Leber Congenital Amaurosis
Fibrosis
Mutation
Liver
Kidney Tubules
Genes
Cystic Kidney Diseases
Respiratory Mucosa
Polycystic Kidney Diseases
Cerebellar Ataxia
Epiphyses
Proteins
Methylprednisolone
Biliary Tract
Missense Mutation
Renal Insufficiency
Retina
Young Adult
Chromosomes

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

Olbrich, H., Fliegauf, M., Hoefele, J., Kispert, A., Otto, E., Volz, A., ... Omran, H. (2003). Mutations in a novel gene, NPHP3, cause adolescent nephronophthisis, tapeto-retinal degeneration and hepatic fibrosis. Nature Genetics, 34(4), 455-459. https://doi.org/10.1038/ng1216

Mutations in a novel gene, NPHP3, cause adolescent nephronophthisis, tapeto-retinal degeneration and hepatic fibrosis. / Olbrich, Heike; Fliegauf, Manfred; Hoefele, Julia; Kispert, Andreas; Otto, Edgar; Volz, Andreas; Wolf, Matthias T.; Sasmaz, Gürsel; Trauer, Ute; Reinhardt, Richard; Sudbrak, Ralf; Antignac, Corinne; Gretz, Norbert; Walz, Gerd; Schermer, Bernhard; Benzing, Thomas; Hildebrandt, Friedhelm; Omran, Heymut.

In: Nature Genetics, Vol. 34, No. 4, 01.08.2003, p. 455-459.

Research output: Contribution to journalArticle

Olbrich, H, Fliegauf, M, Hoefele, J, Kispert, A, Otto, E, Volz, A, Wolf, MT, Sasmaz, G, Trauer, U, Reinhardt, R, Sudbrak, R, Antignac, C, Gretz, N, Walz, G, Schermer, B, Benzing, T, Hildebrandt, F & Omran, H 2003, 'Mutations in a novel gene, NPHP3, cause adolescent nephronophthisis, tapeto-retinal degeneration and hepatic fibrosis', Nature Genetics, vol. 34, no. 4, pp. 455-459. https://doi.org/10.1038/ng1216
Olbrich, Heike ; Fliegauf, Manfred ; Hoefele, Julia ; Kispert, Andreas ; Otto, Edgar ; Volz, Andreas ; Wolf, Matthias T. ; Sasmaz, Gürsel ; Trauer, Ute ; Reinhardt, Richard ; Sudbrak, Ralf ; Antignac, Corinne ; Gretz, Norbert ; Walz, Gerd ; Schermer, Bernhard ; Benzing, Thomas ; Hildebrandt, Friedhelm ; Omran, Heymut. / Mutations in a novel gene, NPHP3, cause adolescent nephronophthisis, tapeto-retinal degeneration and hepatic fibrosis. In: Nature Genetics. 2003 ; Vol. 34, No. 4. pp. 455-459.
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AU - Gretz, Norbert

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